Prognosis of patients with systemic sclerosis-related interstitial lung disease on the lung transplant waiting list: a retrospective study

Advanced systemic sclerosis-associated interstitial lung disease (SSc-ILD) can be treated with lung transplantation. There is limited data on lung transplantation outcomes in patients with SSc-ILD, in non-Western populations.We assessed survival data of patients with SSc-ILD, on the lung transplant (LT) waiting list, and evaluated post-transplant outcomes in patients from an Asian LT center. In this single-center retrospective study, 29 patients with SSc-ILD, registered for deceased LT at Kyoto University Hospital, between 2010 and 2022, were identified. We investigated post-transplant outcomes in recipients who underwent LT for SSc-ILD, between February 2002 and April 2022. Ten patients received deceased-donor LT (34%), two received living-donor LT (7%), seven died waiting for LT (24%), and ten survived on the waiting list (34%). Median duration from registration to deceased-donor LT was 28.9 months and that from registration to living-donor LT or death was 6.5 months. Analysis of 15 recipients showed improved forced vital capacity with a median of 55.1% at baseline, 65.8% at 6 months, and 80.3% at 12 months post-transplant. The 5-year survival rate for post-transplant patients with SSc-ILD was 86.2%. The higher post-transplant survival rate at our institute than previously reported suggests that lung transplantation is acceptable in Asian patients with SSc-ILD.


Materials & methods
Study participants. Using a lung transplant candidate database, patients with SSc-ILD who were registered for deceased-donor lung transplantation at the Kyoto University Hospital between April 2010 and April 2022 were identified. The diagnosis of SSc was made by rheumatologists based on the American College of Rheumatology (ACR) criteria of 1980 or the ACR/European League Against Rheumatism criteria of 2013 14,15 . The registration criteria for the nationwide Japan Organ Transplant Network (JOTN) are: (1) fulfilling the international listing criteria for lung transplantation and (2) age < 60 years for a single lung transplant and < 55 years for a bilateral lung transplant at the time of registration [16][17][18] . The international listing criteria for lung transplants in patients with ILD are: (1) a rapid decline in pulmonary function over six months, (2) hypoxia, (3) decreased walking distance on the 6-min walk test, (4) pulmonary hypertension (PH), and (5) previous hospitalization due to an acute event (e.g. pneumothorax and acute exacerbation) 16,17,19 . Patients who fulfill one or more of these items are registered on JOTN as candidates for a deceased-donor lung transplant. The algorithm for deceaseddonor lung allocation is based primarily on the time the patient has been on the waiting list. In Japan, due to the shortage of donors, single lung transplantation is the standard procedure used for deceased-donor lung transplants for ILDs, including SSc-ILD and IPF. Bilateral deceased-donor lung transplants are warranted only in cases of active chronic respiratory infection, severe PH, and refractory bilateral pneumothorax. Living-donor lung transplants are an option for selected patients with two voluntary donors if the patient cannot continue waiting for a deceased-donor lung transplant due to the severity of their condition 20 .
Patients aged < 18 years at the time of registration and those registered for re-transplantation were excluded from the study. In addition, to investigate post-transplant outcomes, recipients who underwent lung transplantation (deceased or living donor) for SSc-ILD or IPF at Kyoto University Hospital between February 2002 and April 2022 were identified from the lung transplant recipient database.

Clinical variables.
Clinical variables included in the analysis were patient demographics, body mass index, smoking history, distance in the six-minute walk test, SSc subtypes, organ involvement other than ILD, autoantibody profile, the extent of CT involvement, pulmonary function test results (PFT), previous treatments, and long-term oxygen therapy usage. These baseline parameters were obtained at the time of evaluation for lung transplantation. About the evaluation of CT involvement, the extensive disease was defined based on the Goh's criteria 21 . For other organ involvement, PH was diagnosed if (1) estimated pulmonary artery systolic pressure (ePASP) on transthoracic echocardiogram was 40 mmHg or more or (2) mean pulmonary arterial pressure on right heart catheterization was 25 mmHg or more. Gastrointestinal involvement, such as esophageal dilatation, esophageal motility disorder, or gastroesophageal reflux disease, was screened prior to lung transplantation using upper gastrointestinal endoscopy and high-resolution computed tomography (HRCT), if possible.
Post-transplant evaluation. All lung transplant recipients underwent PFT at 3, 6, and 12 months post-transplant. They also underwent HRCT pre-transplant and post-transplant at either 3 or 6 months and 12 months. After 12 months, the recipients underwent PFT and HRCT every 12 months. The PFT results at the initial evaluation for a lung transplant and those at 6 and 12 months post-transplant were used to evaluate changes in functional impairment.
HRCT images were reviewed under blind conditions by two observers (TH and KT). Pre-and post-transplant HRCT scans were examined for evidence of relapse in the transplant lungs and changes in the native lungs (deterioration, no change, or improvement). In addition, all available post-transplant HRCT images were examined.
Statistical analyses. The Mann-Whitney U and the Fisher's exact tests were used for group comparisons.
A paired t test was used to analyze serial changes in individual patients. Survival time on the waiting list for deceased-donor lung transplants was calculated from the registration date until the patient's death or livingdonor lung transplant. Patients were right-censored at the time of the deceased-donor lung transplant or the last contact. The last observational date was 30 April 2022. A living-donor lung transplant was counted as an event as it represented the emergence of a fatal condition. The cox proportional hazards regression analysis was used to identify the factors predictive of mortality on the waiting list. The post-transplant survival time was calculated from the date of the lung transplant to the patient's death, with patients right-censored at the date of re-  22 . All analyses were two-tailed, and a P-value of < 0.05 was considered statistically significant.
Ethics. All study participants provided informed consent, and the study design was approved by the appropriate ethics review board. Therefore, this observational study (not being a clinical trial) was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board (Kyoto University approval number R1355, R1353, R2401).

Results
Characteristics and prognosis of patients with SSc-ILD registered for deceased-donor lung transplantation. Twenty-nine patients with SSc-ILD registered for deceased-donor lung transplants between April 2010 and April 2022 (Table 1). Of these, ten patients received deceased-donor lung transplants (34%), two received living-donor lung transplants (7%), seven died while waiting for a lung transplant (24%), and the remaining ten survived on the list (34%) (Supplementary Fig. S1). The median waiting time from registration to deceased-donor lung transplant was 28.9 months (range 22.3-30.3). The median duration from registration to living-donor lung transplant or death (events) was 6.5 months (range 4.1-14.7).
Of the patients with SSc-ILD registered for a deceased-donor lung transplant, characteristics of the patients who received a deceased-donor lung (n = 10), a living-donor lung, or those who died on the waiting list (n = 9) are compared in Table 2 to identify associated factors of a worse outcome. PH was more common in patients receiving living-donor lungs and those who died on the waiting list. It was also associated with mortality and switching to living-donor lung transplantation while waiting for a deceased-donor lung (hazard ratio: 10.1; 95% confidence interval: [1.26-81.1], P < 0.01) ( Table 3).

Outcomes of lung transplantation for patients with SSc-ILD. Fifteen patients received a lung trans-
plant for SSc-ILD between February 2002 and April 2022; three patients underwent a deceased-donor bilateral lung transplant, seven underwent a deceased-donor single lung transplant, four had a living-donor bilateral lung transplant, and one had a living-donor single lung transplant ( Supplementary Fig. S1). In addition, three patients received a living-donor lung transplant without registration for a deceased-donor lung transplant. Individual lung transplant cases are summarized in Table 4. All recipients were managed with a combination of corticosteroids (maintenance dose: prednisolone 0.2 mg/kg every two days), calcineurin inhibitors (cyclosporine A or tacrolimus), and mycophenolate mofetil as the standard regimen of post-transplant immunosuppression.

Discussion
In this study, 34% of patients with SSc-ILD on the waiting list received a deceased-donor lung transplant after a median wait time of 28.9 months. A total of 31% of patients on the wait list died or required a living-donor lung transplant as an emergency treatment. Lung transplantation improved pulmonary function and led to the cessation of long-term oxygen therapy in approximately 70% of patients, with no relapse of SSc-ILD in the transplanted To the best of our knowledge, this study is the first to evaluate the outcomes of patients with SSc-ILD registered for deceased-donor lung transplants. Similar studies of patients with IPF on the waiting list for deceaseddonor lung transplants showed that 40-60% of patients died while awaiting transplants [23][24][25][26][27] . We recently reported that in a study of 166 patients on the transplant waiting list (who had ILDs, including SSc-ILD, IPF, and other ILDs), 33% of these patients received a deceased-donor lung transplant 19 . Another study from a single institute in Japan showed lower mortality rates for patients with non-IPF ILD (57.9% of patients with CTD) than those with IPF, 40.4% vs 61.4%, respectively 27 . Our results (deceased-donor lung transplant in one-third of patients and mortality or a living-donor lung transplant in another third) were comparable with the reported outcomes of patients with IPF and other ILDs on the waiting list for a deceased-donor lung transplant in Japan. Thus, registration for deceased-donor lung transplants should be considered for patients with severe SSc-ILD at an appropriate time, as well as for those with IPF and other ILDs.
Approximately one-third of patients with SSc-ILD died or needed living-donor lung transplants as an emergency treatment, if available, during the waiting time for a deceased-donor lung transplant. PH was predictive Table 2. Characteristics of systemic sclerosis-related interstitial lung disease patients with deceased/livingdonor or who died awaiting transplant. 6MWD Six-minute walk distance, ACA anti-centromere antibody, ATA anti-topoisomerase-1 antibody, dcSSc diffuse cutaneous systemic sclerosis, DLCO diffusing capacity of the lungs for carbon monoxide, FVC forced vital capacity, GI gastrointestinal, IQR interquartile range, IVCY intravenous cyclophosphamide, lcSSc limited cutaneous systemic sclerosis, LTOT long-term oxygen therapy, M month/s, PH pulmonary hypertension, PSL prednisolone, RNA ribonucleic acid, RNP ribonucleoprotein, S.D. standard deviation, SRC scleroderma renal crisis, SSc systemic sclerosis, Y year/s. a Gastrointestinal involvement included esophageal dilatation, esophageal motility disorder, and gastroesophageal reflux disease detected using gastrointestinal endoscopy or computed tomography. b Extensive CT involvement was defined based on Goh's criteria (the total disease extent in high-resolution CT > 20% was determined as "extensive"). c Because of low vital capacity, there were three missing data points from the deceased-donor lung transplant group and four missing from the living-donor lung transplant or died awaiting transplant group. www.nature.com/scientificreports/ of these fatal outcomes. The combination of ILD and PH in SSc has been associated with a worse prognosis than ILD or PH alone 28,29 . The 2021 ISHLT consensus document proposed three pulmonary phenotypes of SSc in lung transplant candidates according to the extent of ILD and hemodynamic profiles: predominant ILD, combined ILD-PH, and predominant PH 13 . Earlier waitlisting for a deceased-donor lung transplant may be advisable if a patient with SSc has a combined ILD-PH phenotype.
In 2021, the ISHLT proposed lung transplantation was an acceptable option for selected patients with advanced CTD-ILD, including SSc-ILD, after a long-standing debate lasting decades 13 . Particular concerns for patients with SSc-ILD include an increased risk of CLAD associated with esophageal dysmotility and, consequently, a worse post-transplant survival rate than other ILDs 16,30 . However, high-volume lung transplant centers in both the US and Europe have consistently reported acceptable outcomes of lung transplantation for SSc,the estimated 1-year survival rates post-transplant were 81-100%, and the 5-year survival rates were 61-76% 9-11,31-33 . The risk of CLAD was similar between lung transplants for SSc and those for other ILDs. Esophageal disease in SSc did not affect post-transplant survival compared with lung transplants for recipients with other ILDs 11,31,32 . Our results are consistent with previous reports from the US and European lung transplant centers and support the 2021 ISHLT proposal. This study is the first lung transplantation report in cases of SSc-ILD from a highvolume center in Asia. The estimated 5-year post-transplant survival rate was higher than previous reports from other countries, suggesting that favorable post-transplant outcomes can also be achieved in non-Western high-volume lung transplant centers.
The potential effects of the underlying autoimmune condition on the transplanted tissue have been postulated for SSc and other CTD-ILDs 31,33 . In our study, there was no relapse of ILD in the transplanted lung, although ILD in the native lung was progressive for some patients who received a single lung transplant. No serious extrapulmonary complications associated with SSc, such as renal crisis or bowel pseudo-obstruction, were noted. The 2021 ISHLT consensus document listed cardiac, venous thromboembolism, renal (renal crisis), gastrointestinal, and vascular (Raynaud's phenomenon) involvement as disease-specific extrapulmonary manifestations that require consideration and evaluation prior to lung transplantation for SSc 13 . Although the previous 2014 ISHLT criteria for lung transplantation did not include disease-specific listing criteria for SSc-ILD 16 , patients with either active or uncontrolled extrapulmonary manifestations, severe swallowing/esophageal dysfunction, and active myocarditis were excluded from the registry for lung transplantation. Thus, if transplant candidates are carefully selected, lung transplantation for SSc-ILD can be performed with minimal risk of exacerbating extrapulmonary manifestations. Evaluating extrapulmonary manifestations based on a protocol may facilitate the selection of appropriate transplant candidates and thus improve the post-transplant outcomes of recipients with SSc-ILD.
The functional benefits obtained from lung transplantation, post-transplant survival, and risks should be considered. Our results suggest short-term improvement and maintenance of pulmonary function after lung transplant for patients with SSc-ILD, as shown in Fig. 1. Additionally, more than 60% of patients ceased longterm oxygen therapy post-transplant.
Bilateral lung transplant is the preferred procedure for patients with CTD-ILD because of the theoretical benefit of improved survival and post-operative right ventricular function and better reserve to compensate for any decline in lung function due to CLAD 34 . Despite evidence supporting the superiority of bilateral lung transplantation, single lung transplants are still utilized in some countries and lung transplant centers 34 . In Japan, bilateral lung transplants are restricted to patients with active chronic infection, severe PH, or refractory pneumothorax due to the shortage of deceased donors. About half of the recipients in our cohort received a single lung transplant for SSc-ILD, with similar post-transplant outcomes between bilateral and single procedures. ILD progression in the native lung was observed over time in one-third of the single lung transplant recipients. Posttransplant changes in the native lung may influence long-term outcomes after single lung transplantation 35,36 . The impact of transplant procedures (bilateral vs single) and ILD progression in the native lung (following a single lung transplant) on post-transplant outcomes should be addressed in a larger cohort.
This study had limitations in terms of generalizability. The number of transplant candidates for SSc-ILD was insufficient to investigate the predictors of fatal outcomes on the waiting list. The high frequency of single lung transplants in Japan may have a significant effect on the waiting time for transplants 37 . A single-institution study design may also have biased the post-transplant outcomes. Although the 2021 ISHLT consensus paper proposed

Conclusions
Using data from one of the highest-volume lung transplant centers in a non-Western country, we showed that lung transplantation could be an acceptable treatment for selected patients with severe SSc-ILD. Lung transplant indications for SSc and the appropriate time for referral to lung transplant centers should be determined individually in a disease-specific manner.